Accumulating evidence suggests that in healthy individuals, circulating endothelial progenitor cells, broadly defined as pro-angiogenic cells (PACs), represent a population of bone marrow (BM)-derived stem and progenitor cells responsible for repairing injured tissue and initiating neovasculogenesis (Kawamoto et al., Trends in Cardiovascular Medicine. 2008, 18:33-37; Burt et al., JAMA. 2008, 299:925-936). Potentiation of PAC mobilization, homing, or adhesion, has been shown to ameliorate the development of ischemic injury in animal models (Kawamoto et al., Trends in Cardiovascular Medicine. 2008, 18:33-37; Burt et al., JAMA. 2008, 299:925-936). In addition, blockade of pro-angiogenic cytokines or their signaling pathways is believed to alter PAC function and lead to impaired angiogenesis in response to vascular injury and in end-organ ischemia (Kawamoto et al., Trends in Cardiovascular Medicine. 2008, 18:33-37; Burt et al., JAMA. 2008, 299:925-936). Indeed, reduced levels of circulating PACs and diminished PAC function have been reported and found to correlate with a wide-spectrum of atherosclerotic vascular diseases, including peripheral artery disease (PAD) (Fadini et al., Arterioscler Thromb Vasc Biol. 2006, 26:2140-2146; Vasa et al., Circ Res. 2001, 89:E1-7; Hill et al., [see comment] [reprint in Can J. Cardiol. 2004 August; 20 Suppl B:44B-48B; PMID: 15309205]. New England Journal of Medicine. 2003, 348:593-600).
Several early phase I/II trials have been conducted to assess the efficacy of cell-based therapies to treat patients with PAD, but have yielded mixed results (Kawamoto et al., Trends in Cardiovascular Medicine. 2008, 18:33-37; Burt et al., JAMA. 2008, 299:925-936; Tongers et al., Circulation. 2008, 118:9-16; Tateishi-Yuyama et al., Lancet. 2002, 360:427-435; Rafii et al., Nature Medicine. 2003, 9:702-712; Devanesan et al., Eur J Vasc Endovasc Surg. 2009, 38:475-481). Identification of specific PAC subtypes that are endowed with superior capacity to promote neovascularization may represent a particularly efficacious therapeutic strategy. Among hematopoietic progenitor stem cells, the common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) constitute a population of bone marrow-derived cells that preferentially differentiate into PACs and possess robust angiogenic activity under ischemic conditions in vivo (Wara et al., Blood 2011 Dec. 8; 118(24):6461-4. Epub 2011 Aug. 9). However, the signaling pathways and downstream factors that mediate these pro-angiogenic functions remain poorly understood.